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      Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells

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          Abstract

          In the recent years, it has been demonstrated that the biological activity of mesenchymal stem cells (MSCs) is mediated through the release of paracrine factors. Many of these factors are released into exosomes, which are small membranous vesicles that participate in cell–cell communication. Exosomes from MSCs are thought to have similar functions to MSCs such as repairing and regeneration of damaged tissue, but little is known about the immunomodulatory effect of these vesicles. Based on an extensive bibliography where the immunomodulatory capacity of MSCs has been demonstrated, here we hypothesized that released exosomes from MSCs may have an immunomodulatory role on the differentiation, activation and function of different lymphocyte subsets. According to this hypothesis, in vitro experiments were performed to characterize the immunomodulatory effect of human adipose MSCs derived exosomes (exo-hASCs) on in vitro stimulated T cells. The phenotypic characterization of cytotoxic and helper T cells (activation and differentiation markers) together with functional assays (proliferation and IFN-γ production) demonstrated that exo-hASCs exerted an inhibitory effect in the differentiation and activation of T cells as well as a reduced T cell proliferation and IFN-γ release on in vitro stimulated cells. In summary, here we demonstrate that MSCs-derived exosomes are a cell-derived product that could be considered as a therapeutic agent for the treatment of inflammation-related diseases.

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          Most cited references48

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          Standardization of sample collection, isolation and analysis methods in extracellular vesicle research

          The emergence of publications on extracellular RNA (exRNA) and extracellular vesicles (EV) has highlighted the potential of these molecules and vehicles as biomarkers of disease and therapeutic targets. These findings have created a paradigm shift, most prominently in the field of oncology, prompting expanded interest in the field and dedication of funds for EV research. At the same time, understanding of EV subtypes, biogenesis, cargo and mechanisms of shuttling remains incomplete. The techniques that can be harnessed to address the many gaps in our current knowledge were the subject of a special workshop of the International Society for Extracellular Vesicles (ISEV) in New York City in October 2012. As part of the “ISEV Research Seminar: Analysis and Function of RNA in Extracellular Vesicles (evRNA)”, 6 round-table discussions were held to provide an evidence-based framework for isolation and analysis of EV, purification and analysis of associated RNA molecules, and molecular engineering of EV for therapeutic intervention. This article arises from the discussion of EV isolation and analysis at that meeting. The conclusions of the round table are supplemented with a review of published materials and our experience. Controversies and outstanding questions are identified that may inform future research and funding priorities. While we emphasize the need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results, we also recognize that continual development and evaluation of techniques will be necessary as new knowledge is amassed. On many points, consensus has not yet been achieved and must be built through the reporting of well-controlled experiments.
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            Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth.

            Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit for the treatment of neurological diseases and injury. MSCs interact with and alter brain parenchymal cells by direct cell-cell communication and/or by indirect secretion of factors and thereby promote functional recovery. In this study, we found that MSC treatment of rats subjected to middle cerebral artery occlusion (MCAo) significantly increased microRNA 133b (miR-133b) level in the ipsilateral hemisphere. In vitro, miR-133b levels in MSCs and in their exosomes increased after MSCs were exposed to ipsilateral ischemic tissue extracts from rats subjected to MCAo. miR-133b levels were also increased in primary cultured neurons and astrocytes treated with the exosome-enriched fractions released from these MSCs. Knockdown of miR-133b in MSCs confirmed that the increased miR-133b level in astrocytes is attributed to their transfer from MSCs. Further verification of this exosome-mediated intercellular communication was performed using a cel-miR-67 luciferase reporter system and an MSC-astrocyte coculture model. Cel-miR-67 in MSCs was transferred to astrocytes via exosomes between 50 and 100 nm in diameter. Our data suggest that the cel-miR-67 released from MSCs was primarily contained in exosomes. A gap junction intercellular communication inhibitor arrested the exosomal microRNA communication by inhibiting exosome release. Cultured neurons treated with exosome-enriched fractions from MSCs exposed to 72 hours post-MCAo brain extracts significantly increased the neurite branch number and total neurite length. This study provides the first demonstration that MSCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes. Copyright © 2012 AlphaMed Press.
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              MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease.

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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/191128
                URI : http://frontiersin.org/people/u/56922
                URI : http://frontiersin.org/people/u/50424
                URI : http://frontiersin.org/people/u/191120
                URI : http://frontiersin.org/people/u/191125
                URI : http://frontiersin.org/people/u/169130
                URI : http://frontiersin.org/people/u/84942
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                04 November 2014
                2014
                : 5
                : 556
                Affiliations
                [1] 1Stem Cell Therapy Unit, Minimally Invasive Surgery Centre Jesus Uson , Cáceres, Spain
                [2] 2Research and Development Department, TiGenix SA, Parque Tecnológico de Madrid , Madrid, Spain
                [3] 3Technical Operations, TiGenix NV , Leuven, Belgium
                [4] 4Immunology Unit, Department of Physiology, University of Extremadura , Cáceres, Spain
                Author notes

                Edited by: Ana Maria Merino, Bellvitge Biomedical Research Institute (IDIBELL), Spain

                Reviewed by: Maria Cristina Cuturi, INSERM, France; Martin Johannes Hoogduijn, Erasmus Medical Center, Netherlands

                *Correspondence: Javier G. Casado, Stem Cell Therapy Unit, Minimally Invasive Surgery Centre Jesus Uson, Ctra. N-521 Km 41.8, Caceres 10071, Spain e-mail: jgarcia@ 123456ccmijesususon.com

                This article was submitted to Immunotherapies and Vaccines, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00556
                4220146
                25414703
                b1ca4d8b-2e68-4fbd-908d-908dcdb7bc4a
                Copyright © 2014 Blazquez, Sanchez-Margallo, de la Rosa, Dalemans, Álvarez, Tarazona and Casado.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 July 2014
                : 20 October 2014
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 47, Pages: 9, Words: 6406
                Categories
                Immunology
                Original Research

                Immunology
                exosomes,mesenchymal stem cells,immunomodulation,lymphocytes,lymphocyte activation
                Immunology
                exosomes, mesenchymal stem cells, immunomodulation, lymphocytes, lymphocyte activation

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